Neuromodulation for neuroinflammation treatments with parameters controlled using biomarkers

ABSTRACT

An example of a system for modulating neuroinflammation at a tissue site in a patient includes a neuromodulation output circuit, a memory, and a control circuit. The neuromodulation output circuit may be configured to deliver the neuromodulation. The memory may be configured to store a neuromodulation parameter set selected to modulate neural activity at the tissue site and a sensed biomarker parameter. The biomarker parameter may include a measure of a biomarker or a measure of a derivative of the biomarker. The biomarker may be indicative of the neuroinflammation at the tissue site. The control circuit may be configured to control the delivery of the neuromodulation using the neuromodulation parameter set and adjust one or more parameters of the neuromodulation parameter set using the biomarker parameter.

CLAIM OF PRIORITY

This application claims the benefit of priority under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 62/257,457, filed onNov. 19, 2015, which is herein incorporated by reference in itsentirety.

TECHNICAL FIELD

This document relates generally to medical systems, and moreparticularly, to systems and methods for delivering neuromodulation totreat neuroinflammation and controlling the delivery of theneuromodulation using sensed biomarkers.

BACKGROUND

Neuromodulation, also referred to as neurostimulation, has been proposedas a therapy for a number of conditions. Examples of neuromodulationinclude Spinal Cord Stimulation (SCS), Deep Brain Stimulation (DBS),Peripheral Nerve Stimulation (PNS), and Functional ElectricalStimulation (FES). Implantable neuromodulation systems have been appliedto deliver such a therapy. An implantable neuromodulation system mayinclude an implantable neurostimulator, also referred to as animplantable pulse generator (IPG), and one or more implantable leadseach including one or more electrodes. The implantable neurostimulatordelivers neuromodulation energy through one or more electrodes placed onor near a target site in the nervous system. An external programmingdevice is used to program the implantable neurostimulator withstimulation parameters controlling the delivery of the neuromodulationenergy.

Neuromodulation energy may be delivered in any form of energy that iscapable of modulating characteristics of nervous tissue and/orelectrical activities in the nervous system by stimulating target sitesin the nervous system. The delivery may be controlled using stimulationparameters that specify spatial (where to stimulate), temporal (when tostimulate), and informational (patterns of pulses directing the nervoussystem to respond as desired) aspects of a pattern of neuromodulationpulses. Recent research has shown new schemes for setting and adjustingsuch parameters to expand the indications for neuromodulation as well asto improve efficacy of neuromodulation therapies.

SUMMARY

An example (e.g., “Example 1”) of a system for modulatingneuroinflammation at a tissue site in a patient includes aneuromodulation output circuit, a memory, and a control circuit. Theneuromodulation output circuit may be configured to deliver theneuromodulation. The memory may be configured to store a neuromodulationparameter set selected to modulate neural activity at the tissue siteand a sensed biomarker parameter. The biomarker parameter may include ameasure of a biomarker or a measure of a derivative of the biomarker.The biomarker may be indicative of the neuroinflammation at the tissuesite. The control circuit may be configured to control the delivery ofthe neuromodulation using the neuromodulation parameter set and adjustone or more parameters of the neuromodulation parameter set using thebiomarker parameter.

In Example 2, the subject matter of Example 1 may optionally beconfigured such that the control circuit is configured to compare thebiomarker parameter to a reference value and to adjust theneuromodulation parameter set using an outcome of the comparison.

In Example 3, the subject matter of any one or any combination ofExamples 1 and 2 may optionally be configured to include an implantableneuromodulation device. The implantable neuromodulation device mayinclude the neuromodulation output circuit, the memory, and the controlcircuit.

In Example 4, the subject matter of any one or any combination ofExamples 1-3 may optionally be configured to further include a biomarkersensor configured to sense the biomarker parameter.

In Example 5, the subject matter of Example 4 may optionally beconfigured such the biomarker sensor includes an implantable biomarkersensor.

In Example 6, the subject matter of any one or any combination ofExamples 4 and 5 may optionally be configured such that the biomarkersensor is configured to sense the biomarker parameter being a measure ofa translocator protein concentration.

In Example 7, the subject matter of any one or any combination ofExamples 4 and 5 may optionally be configured such that the biomarkersensor is configured to sense the biomarker parameter being a measure ofa temporal activation of the microglial cell.

In Example 8, the subject matter of any one or any combination ofExamples 4 and 5 may optionally be configured such that the biomarkersensor is configured to sense the biomarker parameter being a measure ofa spatial activation of the microglial cell.

In Example 9, the subject matter of any one or any combination ofExamples 4 and 5 may optionally be configured such that the biomarkersensor is configured to sense the biomarker parameter being a measure ofor a cytokine concentration.

In Example 10, the subject matter of any one or any combination ofExamples 4-9 may optionally be configured such that the biomarker sensoris configured to sense a biomarker parameter indicative of a degree ofthe neuroinflammation at the tissue site.

In Example 11, the subject matter of Example 10 may optionally beconfigured such that the biomarker sensor is configured to sense abiomarker parameter indicative of an intensity of pain.

In Example 12, the subject matter of any one or any combination ofExamples 4-11 may optionally be configured such that the biomarkersensor is configured to sense a biomarker parameter indicative of a needfor treating the neuroinflammation.

In Example 13, the subject matter of any one or any combination ofExamples 4-9 may optionally be configured such that the neuromodulationoutput circuit is configured to deliver electrical pulses.

In Example 14, the subject matter of any one or any combination ofExamples 4-9 may optionally be configured to include a neuromodulationdelivery device configured to deliver stimuli including one or more ofelectrical stimuli, magnetic stimuli, optical stimuli, acoustic stimuli,and chemical stimuli, and that the neuromodulation output circuit isconfigured to deliver the neuromodulation by controlling the delivery ofthe stimuli from the neuromodulation delivery device.

In Example 15, the subject matter of Example 14 may optionally beconfigured such that the neuromodulation delivery device is configuredto emit a light, and wherein the neuromodulation output circuit isconfigured to deliver the neuromodulation by controlling the emission ofthe light from the neuromodulation delivery device.

In an example (e.g., “Example 16”), a method for deliveringneuromodulation to a patient is disclosed. The method may includedelivering the neuromodulation; controlling the delivery of theneuromodulation using a neuromodulation parameter set selected tomodulate neural activity at a tissue site; sensing a biomarkerparameter, and adjusting the neuromodulation parameter set using thebiomarker parameter. The biomarker parameter may be a measure of abiomarker or a measure of a derivative of the biomarker. The biomarkermay be indicative of neuroinflammation at the tissue site.

In Example 17, the subject matter of Example 16 may optionally beconfigured such that the biomarker is indicative of activation ofmicroglial cells in the tissue site.

In Example 18, the subject matter of adjusting the neuromodulationparameter set using the biomarker parameter as found in any one or anycombination of Examples 16 and 17 may optionally include comparing thebiomarker parameter to a reference value and adjusting theneuromodulation parameter set using an outcome of the comparison.

In Example 19, the subject matter of the biomarker as found in any oneor any combination of Examples 16-18 may optionally include at least oneof a translocator protein concentration, a temporal activation of themicroglial cell, a spatial activation of the microglial cell, or acytokine concentration.

In Example 20, the subject matter of delivering the neuromodulation asfound in any one or any combination of Examples 16-19 may optionallyinclude delivering electrical pulses.

In Example 21, the subject matter of delivering the neuromodulation asfound in any one or any combination of Examples 16-20 may optionallyinclude emitting a light.

In Example 22, the subject matter of delivering the neuromodulation asfound in any one or any combination of Examples 16-21 may optionallyinclude delivering the neuromodulation to at least one of a dorsalcolumn, a thalamus, a cortex, a peripheral nerve, a vagus nerve, adorsal root ganglion, a dorsal longitudinal fasciculus, or a dorsalhorn.

In Example 23, the subject matter of delivering the neuromodulation asfound in any one or any combination of Examples 16-21 may optionallyinclude delivering the neuromodulation to the tissue site.

In Example 24, the subject matter of delivering the neuromodulation asfound in any one or any combination of Examples 16-21 may optionallyinclude delivering the neuromodulation to an upstream or downstreampathway relative to the tissue site.

In Example 25, the subject matter of delivering the neuromodulation asfound in any one or any combination of Examples 16-21 may optionallyinclude delivering the neuromodulation to a nerve that modulates theneuroinflammation systemically.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the invention will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof, each of which are not tobe taken in a limiting sense. The scope of the present invention isdefined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various examples are illustrated by way of example in the figures of theaccompanying drawings. Such examples are demonstrative and not intendedto be exhaustive or exclusive examples of the present subject matter.

FIG. 1 illustrates an example of a neuromodulation system.

FIG. 2 illustrates an example of a neuromodulation device and a leadsystem of a neuromodulation system, such as the system of FIG. 1.

FIG. 3 illustrates an example of a neuromodulation device and astimulation delivery device of a neuromodulation system, such as thesystem of FIG. 1.

FIG. 4 illustrates an example of a programming device of aneuromodulation system, such as the system of FIG. 1.

FIG. 5 illustrate an example of an implantable neuromodulation systemand portions of an environment in which the system may be used.

FIG. 6 illustrates an example of some features of the neuromodulationleads and a pulse generator.

FIG. 7A illustrates a schematic view of an example of a singleneuromodulation lead implanted over approximately the longitudinalmidline of the patient's spinal cord.

FIG. 7B illustrates a schematic view of an example of an neuromodulationlead that has been implanted more laterally with respect to the spinalcord, thereby placing it proximate the dorsal horn of the spinal cord,and the other neuromodulation lead that has been implanted more mediallywith respect to the spinal cord, thereby placing it proximate the dorsalcolumn of the spinal cord.

FIG. 8 illustrates a schematic view of an example of the neuromodulationlead showing an example of the fractionalization of the anodic currentdelivered to the electrodes on the neuromodulation lead.

FIG. 9 illustrates an example of a method for deliveringneuromodulation.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific examples in which the invention may bepracticed. These examples are described in sufficient detail to enablethose skilled in the art to practice the invention, and it is to beunderstood that the examples may be combined, or that other examples maybe utilized and that structural, logical and electrical changes may bemade without departing from the spirit and scope of the presentinvention. References to “an”, “one”, or “various” examples in thisdisclosure are not necessarily to the same example, and such referencescontemplate more than one example. The following detailed descriptionprovides examples, and the scope of the present invention is defined bythe appended claims and their legal equivalents.

This document discusses, among other things, a system for treatingneuroinflammation in a patient by delivering neuromodulation to a tissuesite in a patient. Neuroinflammation can be inflammation of nervoustissue in the tissue site. The tissue site can include portions of, forexample, dorsal column, thalamus, cortex, peripheral nerve, dorsal rootganglion, dorsal longitudinal fasciculus, dorsal horn, or periaqueductalgrey (PAG). The tissue site can include other targets, such as thosethat modulate inflammation systemically (e.g., a vagus nerve). By way ofexample, neuromodulation can be used to modulate neuroinflammation, suchas by reducing or increasing microglial cell activation in the tissuesite. Such neuromodulation can be used to treat, for example, chronicpain, Alzheimer's disease, unipolar depression, bipolar depression,multiple sclerosis, rheumatoid arthritis, or irritable bowel disease.

Microglia can have metabotropic glu receptors (mGluRs) that allow themicroglia to respond to excitatory neuronal signals. Because mGluRs canmodify microglia phenotype, patterns of activation of glutamanergicneurons may modulate neuroinflammation. A biomarker can be used as ameasure in the patient, which is indicative of a phenomenon, such as theabove mentioned pathologies. A biomarker of the tissue site can includetranslocator protein (TSPO). A measure of TSPO, such as concentration ofTSPO, can be indicative of microglial cell activation. Research hasshown that TSPO may be inversely correlated to chronic pain intensity.The measure of TSPO can be used to classify patients as having, forexample, normal or chronic pain. Cerebrospinal fluid (CSF) levels ofTSPO can be detected using an implantable sensor system to determine asurrogate measure of pain intensity. In an example, TSPO levels at atissue site can be detected using an implantable sensor system, and thedetected level of TSPO at the tissue site can be used a surrogate forpain intensity of the patient. In one example, a signal corresponding toTSPO levels at the tissue site can be used to screen a patient todetermine whether the patient would be a candidate for deviceimplantation.

The present system delivers neuromodulation for modulating neuralactivities at the tissue site of the patient. The system can deliver theneuromodulation and sense the biomarker in the surrounding environmentfor indicating the patient's response to the delivery of theneuromodulation. The system can store patient data, such as a biomarkerparameter associated with the tissue site, and can compare the biomarkerparameter to a reference value. Based on the comparison, the system canadjust a parameter set controlling the delivery of the neuromodulation.As used in this document, a “biomarker parameter” can include a measureof the biomarker and/or a measure of a derivative of the biomarker. Invarious examples, one or more biomarker parameters each being a measureof the biomarker or a measure of a derivative of the biomarker can besensed.

Disclosed herein include systems, devices, and methods for optimizingtreatments for a patient. Metrics that quantify neuroinflammation can beused to determine optimal stimulation targets and parameters for theneuromodulation (e.g., temporal and spatial parameters in a parameterset), and to ensure therapy longevity. Examples of a biomarker caninclude a neuroinflammatory measure that quantifies microglialactivation at a tissue site; cytokine concentration in the cerebrospinalfluid (CSF), dorsal horn, brain ventricles, or brain tissue; ortranslocator protein (TSPO) levels in the dorsal horn, CSF, brain,ventricles, dorsal root ganglion (DRG). One application of the presentsubject matter can include determining patient-specific treatmentapproaches to meet a desired therapeutic goal.

In various examples, neuromodulation as discussed in this document mayuse electrical, magnetic, optical, acoustic, chemical, pharmacological,and/or any other forms of energy or modality to modulate neuralactivities. While a system for neuromodulation using electrical pulsesand/or light is specifically discussed as examples in this document, thepresent subject matter can be applied in neuromodulation using any formof energy that is known to be capable of modulating neural activitiesand/or nervous tissue properties.

FIG. 1 illustrates an example of a neuromodulation system 100. Theillustrated system 100 includes a programming device 102, aneuromodulation device 104, electrodes 106, and one or more biomarkersensors 110. The neuromodulation device 104 can be an external deviceoperable external to the patient or an implantable device placed withinthe patient. The neuromodulation device 104 is configured to beelectrically connected to the electrodes 106 and deliver neuromodulationenergy, such as in the form of electrical pulses, to the tissue sitethrough the electrodes 106. In one example, the neuromodulation device104 is configured to deliver neuromodulation energy in the form oflight, such as using an optical stimulator (e.g., an optical emitter oran optical modulator). The delivery of the neuromodulation is controlledusing a neuromodulation parameter set. The neuromodulation parameter setcan include one or more neuromodulation parameters, such as aneuromodulation parameter specifying an aspect of the electrical pulsesor a selection of electrodes through which each of the electrical pulsesis delivered.

The neuromodulation parameters (also referred to as “the parameters”)can define a neuromodulation pattern (or waveform of stimuli), such as astochastic pattern, a burst pattern, a frequency modulated pattern, apulse width modulated pattern, an amplitude modulated pattern, or abiomimetic pattern. In an example, a biomimetic pattern includes acombination of two or more patterns, such as a stochastic pattern and arate modulated pattern. In one example, the neuromodulation pattern canbe a dynamic pattern that can change over time, such as in response tochanging results of measurement of a biomarker of the tissue site.

In various examples, at least some parameters of the neuromodulationparameter set are user-programmable parameters that are controllable bya user, such as a physician or other caregiver. The programming device102 can provide the user with accessibility to the user-programmableparameters. In various examples, the programming device 102 isconfigured to be communicatively coupled to the neuromodulation device104 via a wired or wireless link. In the illustrated example, theprogramming device 102 includes a graphical user interface (GUI) 108that allows the user to set or adjust values of the user-programmableneuromodulation parameters.

The one or more biomarker sensors 110 can each be configured for sensingone or more biomarker parameters associated with a tissue site. Thebiomarker parameters can each include a measure of the biomarker or ameasure of a derivative of the biomarker. In various examples, thebiomarker parameter is indicative the presence and/or amount of abiomarker in the tissue site, such as a concentration of the biomarkerat the tissue site. In one example, the one or more biomarker sensors110 include one or more implantable biomarker sensors.

FIG. 2 illustrates an example of a neuromodulation device 202 connectedto a lead system 214, such as can be implemented as the neuromodulationdevice 104 in the neuromodulation system 100. The illustrated example ofthe neuromodulation device 202 includes a neuromodulation output circuit204, a neuromodulation control circuit 206 with a processor 208, and amemory 210 with a neuromodulation parameter set 212. The neuromodulationdevice 202 can include other components, such as sensing circuitry forpatient monitoring or feedback control of the therapy, telemetrycircuitry, or power. The neuromodulation output circuit 204 isconfigured to produce and deliver neuromodulation pulses. Theneuromodulation control circuit 206 is configured to control thedelivery of the neuromodulation pulses using one or more neuromodulationparameters of the neuromodulation parameter set 212. In variousexamples, the neuromodulation control circuit 206 is configured toreceive the one or more biomarker parameters from the one or morebiomarker sensors 110 and control the neuromodulation pulses using theone or more biomarker parameters. For example, the processor 208 can beconfigured to adjust one or more parameters of the neuromodulationparameter set 212 in response to a change in the one or more biomarkerparameters.

The lead system 214 can include one or more leads each configured to beelectrically connected to the neuromodulation device 202. The leadsystem 214 can include a plurality of electrodes 216-1 to 216-N (whereN≧2) distributed in an electrode arrangement using the one or moreleads. Each lead can have an electrode array consisting of two or moreelectrodes, which also can be referred to as contacts. Multiple leadscan provide multiple electrode arrays to provide the electrodearrangement. Each electrode in a single electrically conductive contactproviding for an electrical interface between the neuromodulation outputcircuit 204 and tissue of the patient (e.g., the tissue site, or neuraltarget). The neuromodulation pulses are each delivered from theneuromodulation output circuit 204 through a set of electrodes selectedfrom the electrodes 216-1 to 216-N. The number of leads and the numberof electrodes on each lead may depend on, for example, the distributionof targets of the neuromodulation and the need for controlling thedistribution of electric field at each target. In an example, the leadsystem 214 can include two leads each having eight electrodes.

The neuromodulation system 100 can be configured to modulate spinaltarget tissue, brain tissue, or other neural tissue. For example, theneuromodulation system 100 can be configured to modulate neuralactivities at a tissue site such as in a dorsal column, a thalamus, acortex, a peripheral nerve, a dorsal respiratory group, a dorsallongitudinal fasciculus, a dorsal horn, a vagus nerve, or aperiaqueductal grey. The configuration of electrodes used to deliverelectrical pulses to the tissue site (or another location associatedwith the neural activities at the tissue site) constitutes an electrodeconfiguration, with the electrodes capable of being selectivelyprogrammed to act as anodes (positive), cathodes (negative), or left off(zero). In other words, an electrode configuration can represent thepolarity being positive, negative, or zero. The neuromodulationparameter set includes parameters specifying the electrodeconfiguration. Other parameters of the neuromodulation parameter setinclude, for example, the amplitude, pulse width, and rate (orfrequency) of the electrical pulses. Each neuromodulation parameter set,including fractionalized current distribution to the electrodes (aspercentage cathodic current, percentage anodic current, or off), may bestored, such as using the memory 210, and combined into aneuromodulation program that can then be used to modulate the tissuesite or multiple regions within the patient.

The number of electrodes available combined with the ability to generatea variety of complex electrical pulses, presents a huge selection ofneuromodulation parameter sets to the clinician or patient. For example,if the neuromodulation system to be programmed has sixteen electrodes,millions of modulation parameter sets may be available for programminginto the neuromodulation system. Furthermore, for example SCS systemsmay have thirty-two electrodes which exponentially increases the numberof modulation parameters sets available for programming. To facilitatesuch selection, the clinician generally programs the modulationparameters sets through a computerized programming system to allow moredesirable modulation parameters to be determined based on patientfeedback or other means and to subsequently program the desiredmodulation parameter sets.

FIG. 3 illustrates an example of a neuromodulation device 302, such ascan be implemented as the neuromodulation device 104 in theneuromodulation system 100 of FIG. 1. In this example, theneuromodulation device 302 can be coupled to a stimulation deliverydevice 314. Stimulation delivery device 314 provides for an interfacebetween neuromodulation device and the tissue site and produces stimulicapable of modulating neural activities and/or nervous tissue propertiesat the tissue site. Lead system 214 including electrodes 216 is oneexample of stimulation delivery device 314 when electrical stimuli areused for the neuromodulation. In various examples, stimulation deliverydevice 314 can be configured to deliver electrical, magnetic, optical,acoustic, chemical, pharmacological, and/or any other forms of stimuli.

In one example, neuromodulation energy may be delivered in the form ofoptical stimulation, in addition to or in place of the electrodestimulation. Stimulation delivery device 314 includes one or more lightemitters to deliver optical stimuli for the neuromodulation. Forexample, infrared (IR) or near-IR energy deposition can be delivered tothe tissue site, such as to provide anti-inflammatory effects. In oneexample, the one or more light emitters is configured to apply near-IRenergy to the tissue site (e.g., the spinal cord or a brain target),such as to reduce inflammation and promote neuro-proliferation andneuro-regeneration.

In various examples, neuromodulation energy can be delivered in the formof electrical stimulation, magnetic stimulation, optical stimulation,acoustic stimulation, chemical or pharmacological stimulation, or acombination of two or more of such stimulations. Stimulation deliverydevice 314 can include one or more of lead and/or electrodes such aslead system 214 to deliver electrical stimuli such as electrical pulses,one or more electromagnets to deliver magnetic stimuli, one or morelight emitters to deliver optical stimuli such as in the form of IR ornear-IR energy, one or more acoustic energy emitters to deliver acousticstimuli such as in the form of ultrasonic energy, and one or more drugdelivery devices to deliver one or more chemical or pharmacologicaltherapy agents. In an example, the neuromodulation output circuit 204 isconfigured to control delivery of stimulation from stimulation deliverydevice 314. In various examples, the present subject matter can be usedto treat demyelinating, neurodegenerative, or neuroinflammatory diseases(e.g., such as multiple sclerosis, amyotrophic lateral sclerosis,Alzheimer's, depression, chronic pain, central pain, or fibromyalgia).neuromodulation.

The present subject matter can include determining an optimal tissuesite for delivering the neuromodulation to treat a particular disease.In one example, the neuromodulation device (e.g., 104, 202, or 302) usesa quantitative measure of neuroinflammation at a tissue site to screenfor an optimal stimulation target. The quantitative measure used canalso be referred to as the biomarker parameter (which can be measure ofa biomarker or a measure of a derivative of the biomarker) for thetissue site. By way of example, the biomarker can be a concentration ofTSPO, temporal or spatial activation of microglial cells (also referredto as microglia), or a cytokine concentration in one or more particulartissue sites. In one example, the measure of the biomarker can be aquantification of microglial cell activation, such as can be associatedwith an amount of neuroinflammation in the dorsal horn or another tissuesite. In one example, the biomarker parameter can be a cytokineconcentration in the CSF, dorsal horn, brain ventricles, or anotherbrain tissue. In one example, the biomarker parameter can be aquantification of TSPO levels in the dorsal horn, CSF, brain tissue,brain ventricles, the DRG, or another tissue site.

In one example, the biomarker parameter is a spatial measure that can beused to determine a spatial parameter used to control the delivery ofneuromodulation. The spatial measure can be indicative of a spatialdistribution of the biomarker for the tissue site. In an example, thebiomarker parameter is a temporal measure that can be used to determinea temporal parameter used to control the delivery of theneuromodulation. The temporal measurement can be indicative of a changein the biomarker over time for the tissue site. The parameter caninclude a spatiotemporal parameter, such as can be determined using thespatial measurement and the temporal measurement of the biomarker.

In an example, the biomarker can be a metabolic biomarker. In thisexample, the biomarker parameter can be a measure of metabolism of thepatient at a particular tissue site through quantification of ATP or aderivative (e.g., ADP, oxygen consumption, lactate, or pyruvate). For aneuroinflammatory condition, spatially-averaged cellular metabolicdemand can increase relative to metabolic demand of a non-affectedsites. The neuromodulation device can use the measure of the metabolismas the biomarker parameter, such as to determine a locus (e.g., centeror region of high concentration) of neuroinflammation. A potentialadvantage of the present subject matter can include using the biomarkerparameter to optimize neuromodulation targeting.

The present subject matter can include using the biomarker parameter toinform a treatment for the patient, such as an intervention thatalleviates oxidative stress conditions (e.g., increasing the clearanceof instigators of neuroinflammation, such as inflammatory cytokinesthrough increase in blood flow). In an example, the treatment can bedelivering neuromodulation to the inflamed tissue site. Suchneuromodulation can be electrical or optical in nature. In an example,the neuromodulation is delivered to the tissue site. In an example, theneuromodulation is delivered via an upstream or downstream pathway(e.g., a descending inhibitory pathway involving the PAG or the DLF). Inexample, the neuromodulation is delivered to a tissue site thatmodulates inflammation systemically, such as to a site in the vagusnerve.

In one example, the biomarker can be measured using a sensor, which canbe an implantable or external sensing system. In one example, thebiomarker can be measured using an imaging system, such as a PET/MRIscanner, or other imaging modality. In this example, a radioligand canbe used (e.g., a TSPO radioligand such as C-PBR28, C-(R)-PK 11195, orPBR28). In various examples, the one or more biomarker sensors 110represent such implantable or external sensing system or imaging system.The neuromodulation control circuit 206 can be configured to receive oneor more biomarker parameters from the one or more biomarker sensors 110and control the delivery of the neuromodulation using the one or morebiomarker parameters. For example, the processor 208 can be configuredto adjust one or more parameters of the neuromodulation parameter set212 in response to a change in the one or more biomarker parameters. Theneuromodulation parameter set 212 defines the waveform of stimuli usedin the neuromodulation, such as electrical, magnetic, optical, acoustic,chemical, pharmacological, and/or any other forms of stimuli.

FIG. 4 illustrates an example of a programming device 402, such as canbe implemented as the programming device 102 in the neuromodulationsystem 100. The programming device 402 can include a memory or storagedevice 410 that can be referred to as storage, a programming controlcircuit 408, and a GUI 404. In the illustrated example, the GUI 404includes a touchscreen 406. The programming control circuit 408 can beused to generate the neuromodulation parameter set (e.g., 212) thatcontrols the delivery of the neuromodulation. In various examples, theGUI 404 can include any type of presentation device, such as interactiveor non-interactive screens, and any type of user input devices thatallow the user to program the user-programmable parameters of theneuromodulation parameter set, such as touchscreen, keyboard, keypad,touchpad, trackball, joystick, and mouse. The storage device 410 canstore, among other things, the neuromodulation parameter set to beprogrammed into the neuromodulation device (e.g., 102, 202, or 302). Theprogramming device 402 can transmit parameters of the neuromodulationparameter set to the neuromodulation device (e.g., 104, 202, or 302). Insome examples, the programming device 402 can also transmit power to theneuromodulation device (e.g., 104, 202, or 302). The programming controlcircuit 408 can generate parameters of the neuromodulation parameterset. In various examples, the programming control circuit 408 may checkvalues of certain parameters of the neuromodulation parameter setagainst safety rules to limit these values within constraints of thesafety rules.

In some example, the neuromodulation control circuit 206 is configuredto receive one or more biomarker parameters from the one or morebiomarker sensors 110 and control the delivery of the neuromodulationusing the one or more biomarker parameters, as discussed above. Forexample, programming device 402 can program the neuromodulationparameter set 212 into memory 210, and the neuromodulation controlcircuit 206 can adjust one or more parameters of the neuromodulationparameter set 212 in response to a change in the one or more biomarkerparameters. In some other examples, the programming device 402 can beconfigured to receive one or more biomarker parameters sensed by the oneor more biomarker sensors 110 and transmitted from the neuromodulationdevice (e.g., 104, 202, or 302), and the programming control circuit 408can be configured to adjust one or more parameters of theneuromodulation parameter set using the one or more biomarkerparameters. For example, the programming control circuit 408 can beconfigured to adjust one or more parameters of the neuromodulationparameter set 212 in response to a change in the one or more biomarkerparameters. This is useful when, for example, the user (physician orother caregiver) is involved in adjusting the neuromodulation parameterset using the one or more biomarker parameters.

In various examples, circuits of the neuromodulation system 100,including its various examples discussed in this document, may beimplemented using a combination of hardware, software and firmware. Forexample, the circuit of the GUI 404, the neuromodulation control circuit206, and the programming control circuit 408 may be implemented using anapplication-specific circuit constructed to perform one or moreparticular functions or a general-purpose circuit programmed to performsuch function(s). Such a general-purpose circuit includes, but is notlimited to, a microprocessor or a portion thereof, a microcontroller orportions thereof, and a programmable logic circuit or a portion thereof.

FIG. 5 illustrates an example of an implantable neuromodulation system500 and portions of an environment in which the system 500 may be used.The system 500 is illustrated by way of example, but not by way oflimitation, as being implanted near the spinal cord of a patient. Invarious examples, the system 500 can be configured to be implanted invarious locations in the patient to modulate various neural targets,such as the tissue sites for modulating neuroinflammation as discussedin this document. The system 500 can include an implantable system 508,an external system 510, and a telemetry link 512 providing for wirelesscommunication between the implantable system 508 and the external system510. The implantable system 508, illustrated as being implanted in thepatient's body, includes an implantable neuromodulation device (alsoreferred to as an implantable pulse generator, or IPG) 504, a leadsystem 506, and electrodes 502. In various examples, the neuromodulationdevice 104, 202, or 302 can be implemented as the implantableneuromodulation device 504, the lead system 214 can be implemented asthe lead system 506, and the electrodes 106 or 214 can be implemented asthe electrodes 502. The lead system 506 includes one or more leads eachconfigured to be electrically connected to the implantableneuromodulation device 504 and a plurality of electrodes 502 distributedin the one or more leads. In various examples, the external system 510includes one or more external (non-implantable) devices each allowing auser (e.g. a clinician or other caregiver and/or the patient) tocommunicate with the implantable neuromodulation device 504. In variousexamples, the programming device 402 can be implemented as such anexternal device. In some examples, the external system 510 includes aprogramming device intended for a clinician or other caregiver toinitialize and adjust settings for the implantable neuromodulationdevice 504 and a remote control device intended for use by the patient.For example, the remote control device may allow the patient to turn atherapy on and off and/or adjust certain patient-programmable parametersof the plurality of modulation parameters.

The neuromodulation lead(s) of the lead system 506 may be placedadjacent, e.g., resting near, or upon the dura, adjacent to the spinalcord area to be stimulated. For example, the neuromodulation lead(s) maybe implanted along a longitudinal axis of the spinal cord of thepatient. Due to the lack of space near the location where theneuromodulation lead(s) exit the spinal column, the implantablemodulation

FIG. 6 illustrates an example of some features of the neuromodulationleads 604 and a neuromodulation device 602. The neuromodulation device602 may be an implantable device or may be an external. In theillustrated example, one of the neuromodulation leads has eightelectrodes (labeled E1-E8), and the other neuromodulation lead has eightelectrodes (labeled E9-E16). The actual number and shape of leads andelectrodes may vary for the intended application. An implantable devicemay include an outer case for housing the electronic and othercomponents. The outer case may be composed of an electricallyconductive, biocompatible material, such as titanium, that forms ahermetically-sealed compartment wherein the internal electronics areprotected from the body tissue and fluids. In some cases, the outer casemay serve as an electrode (e.g. case electrode).

The implanted device may include electronic components, such as acontroller/processor (e.g., a microcontroller), memory, a battery,telemetry circuitry, monitoring circuitry, modulation output circuitry,and other suitable components known to those skilled in the art. Themicrocontroller executes a suitable program stored in memory, fordirecting and controlling the neuromodulation performed by the implanteddevice.

Electrical neuromodulation energy is provided to the electrodes inaccordance with the neuromodulation parameter set programmed into theneuromodulation device. The neuromodulation energy may be in the form ofa pulsed electrical waveform. Such neuromodulation parameters maycomprise electrode combinations, which define the electrodes that areactivated as anodes (positive), cathodes (negative), and turned off(zero), percentage of neuromodulation energy assigned to each electrode(fractionalized electrode configurations), and electrical pulseparameters, which define the pulse amplitude (measured in milliamps orvolts depending on whether the pulse generator supplies constant currentor constant voltage to the electrode array), pulse width (measured inmicroseconds), pulse rate (measured in pulses per second), and burstrate (measured as the modulation on duration X and modulation offduration Y). The electrical pulse parameters may define an intermittentneuromodulation with “on” periods of time where a train of two or morepulses are delivered and “off” periods of time where pulses are notdelivered. Electrodes that are selected to transmit or receiveelectrical energy are referred to herein as “activated,” whileelectrodes that are not selected to transmit or receive electricalenergy are referred to herein as “non-activated.”

Electrical neuromodulation occurs between or among a plurality ofactivated electrodes, one of which may be a case electrode of theimplanted device. The system may be capable of transmittingneuromodulation energy to the tissue in a monopolar or multipolar (e.g.,bipolar, tripolar, etc.) fashion. Monopolar neuromodulation occurs whena selected one of the lead electrodes is activated along with the caseof the neuromodulation device, so that neuromodulation energy istransmitted between the selected electrode and case.

Any of the electrodes (e.g. E1-E16 and the case electrode) may beassigned to up to k possible groups or timing “channels.” In oneexample, k may equal four. The timing channel identifies whichelectrodes are selected to synchronously source or sink current tocreate an electric field in the tissue to be stimulated. Amplitudes andpolarities of electrodes on a channel may vary. In particular, theelectrodes can be selected to be positive (anode, sourcing current),negative (cathode, sinking current), or off (no current) polarity in anyof the k timing channels.

The neuromodulation device may be configured to individually control themagnitude of electrical current flowing through each of the electrodes,which may be referred to as multiple independent current control (MICC).For example, a current generator may be configured to selectivelygenerate individual current-regulated amplitudes from independentcurrent sources for each electrode. In some examples, the pulsegenerator may have voltage regulated outputs. While individuallyprogrammable electrode amplitudes are desirable to achieve fine control,a single output source switched across electrodes may also be used,although with less fine control in programming. The neuromodulationdevice may be designed with mixed current and voltage regulated devices.The individual control of electrical current through each of theelectrodes allows the neuromodulation device to fractionalize thecurrent. The fractionalization across the neuromodulation lead can varyin any manner as long as the total of fractionalized currents equals100%.

The SCS system may be configured to deliver different electrical fieldsto achieve a temporal summation of modulation. The electrical fields canbe generated respectively on a pulse-by-pulse basis. For example, afirst electrical field can be generated by the electrodes (using a firstcurrent fractionalization) during a first electrical pulse of the pulsedwaveform, a second different electrical field can be generated by theelectrodes (using a second different current fractionalization) during asecond electrical pulse of the pulsed waveform, a third differentelectrical field can be generated by the electrodes (using a thirddifferent current fractionalization) during a third electrical pulse ofthe pulsed waveform, a fourth different electrical field can begenerated by the electrodes (using a fourth different currentfractionalized) during a fourth electrical pulse of the pulsed waveform,and so forth. These electrical fields may be rotated or cycled throughmultiple times under a timing scheme, where each field is implementedusing a timing channel. The electrical fields may be generated at acontinuous pulse rate, or as bursts of pulses. Furthermore, theinterpulse interval (i.e., the time between adjacent pulses), pulseamplitude, and pulse duration during the electrical field cycles may beuniform or may vary within the electrical field cycle. Various examplesstochastically modulate values for one or more neuromodulationparameters such as these and others.

Some examples are configured to provide a neuromodulation parameter setto create a desired neuromodulation field shape (e.g. a broad anduniform neuromodulation field such as may be useful to prime targetedneural tissue with sub-perception modulation or a field shape to reduceor minimize modulation of non-targeted tissue. Various examplesstochastically modulate values of one or more neuromodulation parametersassociated with controlling the field shape in order to stochasticallymodulate the neuromodulation field shape.

FIG. 7A illustrates a schematic view of an example of a singleneuromodulation lead 704 implanted over approximately the longitudinalmidline of the patient's spinal cord 702.

FIG. 7B illustrates a schematic view of an example of an neuromodulationlead 708 that has been implanted more laterally with respect to thespinal cord 706, thereby placing it proximate the dorsal horn (DH) ofthe spinal cord, and the other neuromodulation lead 710 that has beenimplanted more medially with respect to the spinal cord, thereby placingit proximate the dorsal column (DC) of the spinal cord 706.

It is understood that additional leads or lead paddle(s) may be used,such as may be used to provide a wider electrode arrangement and/or toprovide the electrodes closer to dorsal horn elements, and that theseelectrode arrays also may implement fractionalized current. Placement ofthe lead more proximate to the DH than the DC may be desirable topreferentially stimulate DH elements over DC neural elements for asubperception therapy. Lead placement may also enable preferentialmodulation of dorsal roots over other neural elements. Any otherplurality of leads or a multiple column paddle lead can also be used.Longitudinal component of the electrical field is directed along they-axis depicted in FIG. 7A, and a transverse component of the electricalfield is directed along the x-axis depicted in FIG. 7A.

FIG. 8 illustrates a schematic view of an example of the neuromodulationlead 802 showing an example of the fractionalization of the anodiccurrent delivered to the electrodes on the neuromodulation lead. Thisfigure illustrates fractionalization using monopolar modulation where acase electrode of the IPG is the only cathode, and carries 100% of thecathodic current. The fractionalization of the anodic current shown inFIG. 8 does not deliver an equal amount of current to each electrode804, because this example takes into account electrode/tissue couplingdifferences, which are the differences in how the tissue underlying eachelectrode reacts to neuromodulation. Also, the ends of the portion ofthe neuromodulation lead include electrodes having lower gradient in thelongitudinal direction. The magnitude of the electrical field tapersdown at the ends of the neuromodulation lead. Fractionalization of thecurrent may accommodate variation in the tissue underlying thoseelectrodes. The fractionalization across the neuromodulation lead canvary in any manner as long as the total of fractionalized currentsequals 100%. Various examples described herein implement a programmedalgorithm to determine the appropriate fractionalization to achieve adesired modulation field property.

Modulation thresholds vary from patient to patient and from electrode toelectrode within a patient. An electrode/tissue coupling calibration ofthe electrodes may be performed to account for these differentmodulation thresholds and provide a more accurate fractionalization ofthe current between electrodes. For example, perception threshold may beused to normalize the electrodes. The RC or the CP may be configured toprompt the patient to actuate a control element, once paresthesia isperceived by the patient. In response to this user input, the RC or theCP may be configured to respond to this user input by storing themodulation signal strength of the electrical pulse train delivered whenthe control element is actuated. Other sensed parameter orpatient-perceived modulation values (e.g. constant paresthesia, ormaximum tolerable paresthesia) may be used to provide theelectrode/tissue coupling calibration of the electrodes.

The SCS system may be configured to deliver different electrical fieldsto achieve a temporal summation of modulation. The electrical fields canbe generated respectively on a pulse-by-pulse basis. For example, afirst electrical field can be generated by the electrodes (using a firstcurrent fractionalization) during a first electrical pulse of the pulsedwaveform, a second different electrical field can be generated by theelectrodes (using a second different current fractionalization) during asecond electrical pulse of the pulsed waveform, a third differentelectrical field can be generated by the electrodes (using a thirddifferent current fractionalization) during a third electrical pulse ofthe pulsed waveform, a fourth different electrical field can begenerated by the electrodes (using a fourth different currentfractionalized) during a fourth electrical pulse of the pulsed waveform,and so forth. These electrical fields can be rotated or cycled throughmultiple times under a timing scheme, where each field is implementedusing a timing channel. The electrical fields may be generated at acontinuous pulse rate, or as bursts of pulses. Furthermore, theinterpulse interval (i.e., the time between adjacent pulses), pulseamplitude, and pulse duration during the electrical field cycles may beuniform or may vary within the electrical field cycle. Some examples areconfigured to determine a modulation parameter set to create a fieldshape to provide a broad and uniform modulation field such as may beuseful to prime targeted neural tissue with sub-perception modulation.Some examples are configured to determine a modulation parameter set tocreate a field shape to reduce or minimize modulation of non-targetedtissue (e.g., dorsal column tissue). Various examples disclosed hereinare directed to shaping the modulation field to enhance modulation ofsome neural structures and diminish modulation at other neuralstructures. The modulation field may be shaped by using multipleindependent current control (MICC) or multiple independent voltagecontrol to guide the estimate of current fractionalization amongmultiple electrodes and estimate a total amplitude that provide adesired strength. For example, the modulation field may be shaped toenhance the modulation of dorsal horn neural tissue and to minimize themodulation of dorsal column tissue. A benefit of MICC is that MICCaccounts for various in electrode-tissue coupling efficiency andperception threshold at each individual contact, so that “hotspot”stimulation is eliminated.

FIG. 9 illustrates an example of a method 900 of deliveringneuromodulation. In various examples, the neuromodulation system 100 canbe configured to perform the method 900. In various examples, animplantable neuromodulation system (e.g., 500) can be configured toperform the method 900.

At 902, neuromodulation is delivered to a tissue site or anotherlocation that is associated with neural activities at the tissue site,such as from the neuromodulation device 104, 202, or 302. Examples ofthe tissue site include the tissue site for modulating neuroinflammationas discussed in this document.

At 904, the delivery of neuromodulation to the tissue site is controlledusing a neuromodulation parameter set. The neuromodulation parameter setcan include a plurality of neuromodulation parameters that can betemporal or spatial parameters defining a pattern according to which theneuromodulation energy is delivered, such as a waveform including aplurality of electrical pulses.

At 906, one or more biomarker parameters associated with the tissue siteare sensed using one or more biomarker sensors (e.g., 110). The one ormore biomarker parameters each indicate a neural or other physiologicalresponse to the delivery of the neuromodulation. The one or morebiomarkers are each a measure of the biomarker or a measure of aderivative of the biomarker. In one example, the one or more sensedbiomarker parameters are stored, such as in the memory 210.

At 908, one or more biomarker parameters are each compared to areference value, such as by using the processor 208. In an example, thereference value or value range can be a stored value in the memory 210.In one example, the reference value or value range can be a previouslysensed value of the corresponding biomarker parameter. In an example,the reference value can be determined from clinical data, such asobtained during a clinical trial.

At 910, the neuromodulation parameter set are adjusted using an outcomeof the comparison. In one example, the reference value or value rangerepresents a threshold indicative of a need for treatingneuroinflammation, and the outcome of the comparison indicates such aneed. In one example, the reference value or value range represents adegree of neuroinflammation, and the outcome of the comparison indicatesan intensity of the neuromodulation needed for treating theneuroinflammation at the indicted degree.

A potential advantage of the present subject matter can includedetermining patient-specific therapies. The neuromodulation device canaid in determining that, for a first patient “A” with a modulationtarget “X”, a spatiotemporal neuromodulation parameter set “Y” isoptimal for patient “A”. However, for example, the neuromodulationdevice can aid in determining that, for a second patient “B” with amodulation target “U,” a spatiotemporal neuromodulation parameter set“W” is optimal for patient “B.” In an example, the present subjectmatter can be used for therapies of single targets or for multipletargets, such as complex multimodal treatment paradigms (e.g., dorsalcolumn stimulation with neuromodulation parameter set “C” with DRGstimulation with neuromodulation parameter set “D”).

In some examples, the method 900, or variants of any part of the method900, can be implemented as instructions stored in a machine readablestorage medium. The machine can be in a form of a computer system, whichcan include a processor, memory, video display unit, an alpha-numericinput device, and a user interface with a navigation device, a diskdrive unit, a signal generation device, a network interface device,among others. The instructions can cause machine to perform any part ofthe method 900 or any variants thereof. The instructions can also causethe machine for displaying an output.

The machine can operate as a standalone device or may be connected(e.g., networked) to other machines. In a networked deployment, themachine may operate in the capacity of a server or a client machine inserver-client network environment, or as a peer machine in apeer-to-peer (or distributed) network environment. The machine may be apersonal computer (PC), a tablet PC, a set-top box (STB), a PDA, acellular telephone, a web appliance, a network router, switch or bridge,or any machine capable of executing instructions (sequential orotherwise) that specify actions to be taken by that machine. Further,while only a single machine is illustrated, the term “machine” shallalso be taken to include any collection of machines that individually orjointly execute a set (or multiple sets) of instructions to perform anyone or more of the methodologies discussed herein.

The machine-readable medium may include a single medium or multiplemedia (e.g., a centralized or distributed database, and/or associatedcaches and servers) that store the one or more instructions or datastructures. The term “machine-readable storage medium” shall also betaken to include any tangible medium that is capable of storing,encoding or carrying instructions for execution by the machine and thatcause the machine to perform any one or more of the methods of thepresent invention, or that is capable of storing, encoding or carryingdata structures used by or associated with such instructions. The term“machine-readable storage medium” shall accordingly be taken to include,but not be limited to, solid-state memories, and optical and magneticmedia. Specific examples of machine-readable media include non-volatilememory, including by way of example, semiconductor memory devices (e.g.,erasable programmable read-only memory (EPROM), electrically erasableprogrammable read-only memory (EEPROM)) and flash memory devices;magnetic disks such as internal hard disks and removable disks;magneto-optical disks; and CD-ROM and DVD-ROM disks. A “machine-readablestorage medium” shall also include devices that may be interpreted astransitory, such as register memory, processor cache, and RAM, amongothers. The definitions provided herein of machine-readable medium andmachine-readable storage medium are applicable even if themachine-readable medium is further characterized as being“non-transitory.” For example, any addition of “non-transitory,” such asnon-transitory machine-readable storage medium, is intended to continueto encompass register memory, processor cache and RAM, among othermemory devices.

In various examples, the instructions may further be transmitted orreceived over a communications network using a transmission medium. Theinstructions may be transmitted using the network interface device andany one of a number of well-known transfer protocols (e.g., HTTP).Examples of communication networks include a LAN, a WAN, the Internet,mobile telephone networks, plain old telephone (POTS) networks, andwireless data networks (e.g., WiFi and WiMax networks). The term“transmission medium” shall be taken to include any intangible mediumthat is capable of storing, encoding or carrying instructions forexecution by the machine, and includes digital or analog communicationssignals or other intangible media to facilitate communication of suchsoftware.

The above detailed description includes references to the accompanyingdrawings, which form a part of the detailed description. The drawingsshow, by way of illustration, specific examples in which the inventioncan be practiced. These examples are also referred to herein as“examples.” Such examples can include elements in addition to thoseshown or described. However, the present inventors also contemplateexamples in which only those elements shown or described are provided.Moreover, the present inventors also contemplate examples usingcombinations or permutations of those elements shown or described (orone or more aspects thereof), either with respect to a particularexample (or one or more aspects thereof), or with respect to otherexamples (or one or more aspects thereof) shown or described herein.

In the event of inconsistent usages between this document and anydocuments so incorporated by reference, the usage in this documentcontrols.

In this document, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.” In thisdocument, the term “or” is used to refer to a nonexclusive or, such that“A or B” includes “A but not B,” “B but not A,” and “A and B,” unlessotherwise indicated. In this document, the terms “including” and “inwhich” are used as the plain-English equivalents of the respective terms“comprising” and “wherein.” Also, in the following claims, the terms“including” and “comprising” are open-ended, that is, a system, device,article, composition, formulation, or process that includes elements inaddition to those listed after such a term in a claim are still deemedto fall within the scope of that claim. Moreover, in the followingclaims, the terms “first,” “second,” and “third,” etc. are used merelyas labels, and are not intended to impose numerical requirements ontheir objects.

Method examples described herein can be machine or computer-implementedat least in part. Some examples can include a computer-readable mediumor machine-readable medium encoded with instructions operable toconfigure an electronic device to perform methods as described in theabove examples. An implementation of such methods can include code, suchas microcode, assembly language code, a higher-level language code, orthe like. Such code can include computer readable instructions forperforming various methods. The code may form portions of computerprogram products. Further, in an example, the code can be tangiblystored on one or more volatile, non-transitory, or non-volatile tangiblecomputer-readable media, such as during execution or at other times.Examples of these tangible computer-readable media can include, but arenot limited to, hard disks, removable magnetic disks, removable opticaldisks (e.g., compact disks and digital video disks), magnetic cassettes,memory cards or sticks, random access memories (RAMs), read onlymemories (ROMs), and the like.

The above description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or moreaspects thereof) may be used in combination with each other. Otherexamples can be used, such as by one of ordinary skill in the art uponreviewing the above description. The Abstract is provided to comply with37 C.F.R. §1.72(b), to allow the reader to quickly ascertain the natureof the technical disclosure. It is submitted with the understanding thatit will not be used to interpret or limit the scope or meaning of theclaims. Also, in the above Detailed Description, various features may begrouped together to streamline the disclosure. This should not beinterpreted as intending that an unclaimed disclosed feature isessential to any claim. Rather, inventive subject matter may lie in lessthan all features of a particular disclosed example. Thus, the followingclaims are hereby incorporated into the Detailed Description as examplesor examples, with each claim standing on its own as a separate example,and it is contemplated that such examples can be combined with eachother in various combinations or permutations. The scope of theinvention should be determined with reference to the appended claims,along with the full scope of equivalents to which such claims areentitled.

What is claimed is:
 1. A method for delivering neuromodulation to apatient, the method comprising: delivering the neuromodulation;controlling the delivery of the neuromodulation using a neuromodulationparameter set selected to modulate neural activity at a tissue site;sensing a biomarker parameter being a measure of a biomarker or ameasure of a derivative of the biomarker, the biomarker indicative ofneuroinflammation at the tissue site; and adjusting the neuromodulationparameter set using the biomarker parameter.
 2. The method of claim 1,wherein the biomarker is indicative of activation of microglial cells inthe tissue site.
 3. The method of claim 1, wherein adjusting theneuromodulation parameter set using the biomarker parameter comprises:comparing the biomarker parameter to a reference value; and adjustingthe neuromodulation parameter set using an outcome of the comparison. 4.The method of claim 3, wherein the biomarker comprises at least one of atranslocator protein concentration, a temporal activation of themicroglial cell, a spatial activation of the microglial cell, or acytokine concentration.
 5. The method of claim 1, wherein delivering theneuromodulation comprises delivering electrical pulses.
 6. The method ofclaim 1, wherein delivering the neuromodulation comprises emitting alight.
 7. The method of claim 1, wherein delivering the neuromodulationcomprises delivering the neuromodulation to at least one of a dorsalcolumn, a thalamus, a cortex, a peripheral nerve, a vagus nerve, adorsal root ganglion, a dorsal longitudinal fasciculus, or a dorsalhorn.
 8. The method of claim 1, wherein delivering the neuromodulationcomprises delivering the neuromodulation to the tissue site.
 9. Themethod of claim 1, wherein delivering the neuromodulation comprisesdelivering the neuromodulation to an upstream or downstream pathwayrelative to the tissue site.
 10. The method of claim 1, whereindelivering the neuromodulation comprises delivering the neuromodulationto a nerve that modulates the neuroinflammation systemically.
 11. Asystem for modulating neuroinflammation at a tissue site in a patient,the system comprising: a neuromodulation output circuit configured todeliver the neuromodulation; a memory configured to store aneuromodulation parameter set selected to modulate neural activity atthe tissue site and a sensed biomarker parameter, the biomarkerparameter including a measure of a biomarker or a measure of aderivative of the biomarker, the biomarker indicative of theneuroinflammation at the tissue site; and a control circuit configuredto control the delivery of the neuromodulation using the neuromodulationparameter set and adjust one or more parameters of the neuromodulationparameter set using the biomarker parameter.
 12. The system of claim 11,wherein the control circuit is configured to compare the biomarkerparameter to a reference value and to adjust the neuromodulationparameter set using an outcome of the comparison.
 13. The system ofclaim 12, comprising an implantable neuromodulation device including theneuromodulation output circuit, the memory, and the control circuit. 14.The system of claim 12, further comprising a biomarker sensor configuredto sense the biomarker parameter, wherein the biomarker sensor isconfigured to sense the biomarker parameter being a measure of at leastone of a translocator protein concentration, a measure of a temporalactivation of the microglial cell, a measure of a spatial activation ofthe microglial cell, or a measure of or a cytokine concentration. 15.The system of claim 14, wherein the biomarker sensor is configured tosense a biomarker parameter indicative of a degree of theneuroinflammation at the tissue site.
 16. The system of claim 15,wherein the biomarker sensor is configured to sense a biomarkerparameter indicative of an intensity of pain.
 17. The system of claim14, wherein the biomarker sensor is configured to sense a biomarkerparameter indicative of a need for treating the neuroinflammation. 18.The system of claim 11, wherein the neuromodulation output circuit isconfigured to deliver electrical pulses.
 19. The system of claim 11,further comprising a neuromodulation delivery device configured todeliver stimuli including one or more of electrical stimuli, magneticstimuli, optical stimuli, acoustic stimuli, and chemical stimuli, andwherein the neuromodulation output circuit is configured to deliver theneuromodulation by controlling the delivery of the stimuli from theneuromodulation delivery device.
 20. The system of claim 19, wherein theneuromodulation delivery device is configured to emit a light, andwherein the neuromodulation output circuit is configured to deliver theneuromodulation by controlling the emission of the light from theneuromodulation delivery device.